GB2025932A - Indoloisoquinolines, and Processes for Producing them - Google Patents
Indoloisoquinolines, and Processes for Producing them Download PDFInfo
- Publication number
- GB2025932A GB2025932A GB7826749A GB7826749A GB2025932A GB 2025932 A GB2025932 A GB 2025932A GB 7826749 A GB7826749 A GB 7826749A GB 7826749 A GB7826749 A GB 7826749A GB 2025932 A GB2025932 A GB 2025932A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- hydrogen
- compound
- methyl
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Indoloisoquinolines of the formula, <IMAGE> and pharmaceutically acceptable acid addition salts thereof, wherein R1 and R4 are each, independently of one another, hydrogen, halogen, nitro or lower alkoxy and R2 and R3 are each independently of one another, hydrogen, lower alkyl, lower alkenyl, cycloalkylalkyl or a group of the formula, <IMAGE> or -A-O-B wherein A is C1-7 alkylene; R5 and R6 are each, independently of one another, hydrogen or lower alkyl, or together with the adjacent nitrogen atom, form a 5- or 6-membered heterocyclic ring; and B is hydrogen, lower alkyl, lower alkenyl or lower alkanoyl; provided that, when at the same time, each of R1, and R4 is hydrogen and R3 is methyl, then R2 is other than hydrogen, have potent anti-tumour activity. They can be prepared by reacting a compound of the formula, <IMAGE> wherein R1, R3 and R4 are as defined above with a reactive derivative of the formula, R8-OH wherein R8 is lower alkyl, lower alkenyl, cycloalkylalkyl or a group of the formula <IMAGE> or -A-O-B, wherein A, R5, R6 and B are as defined above. Alternatively, when R2 is hydrogen, they can be prepared by heating a compound of the formula <IMAGE> wherein R1, R3 and R4 are as defined above.
Description
SPECIFICATION
Indoloisoquinolines and Processes for
Producing Them
The present invention relates to indoloisoquinolines, and to their preparation.
More particularly, the invention relates to a range of 7H-indolo(2,3-c)isoquinoiines as hereinafter defined, having anti-tumour activity.
It was recently reported that the thermal reaction of 1 -methyl-2-phenylcarba moylamino3- phenyl-indole(ll) or l-methyl-2- ethoxycarbonylamino-3-phenyl-indole(lll) afforded 7-methyl-indolo(2,3-c)isoquinolin5(6H)-one(lV) (Tetrahedron Letters, 1975, 3877).
Up to the present time, however, nothing has been known about the biological activities of the compound of the formula (IV).
We have now succeeded in the synthesis of a range of related indoloisoquinoline compounds and have found that these compounds possess potent anti-tumour activity.
A compound of the present invention has the formula,
wherein R, and R4 are each, independently of one another, hydrogen, halogen, nitro or lower alkoxy
R2 and R3 are each, independently of one another, hydrogen, lower alkyl, lower alkenyl, cycloalkylalkyl or a group of the formula,
or -A-O-B (wherein A is straight or branched C17 alkylene; R5 and R8 are each independently of one another, hydrogen or lower alkyl, or, together with the adjacent nitrogen atom, from a 5- or 6membered heterocyclic ring; and B is hydrogen, lower alkyl, lower alkenyl or lower alkanoyl); or, when R2 is hydrogen, the keto isomer thereof: provided that when, at the same time, each of R, and R4 is hydrogen and R3 is methyl, R2 is other than hydrogen; or a pharmaceutically acceptable acid addition salt thereof.
The halogen atom may be fluorine, chlorine, bromine, or iodine: the lower alkyl group is a C14 straight or branched aliphatic hydrocarbon, and may, for example, be methyl, ethyl, propyl, isopropyl, butyl or isobutyl; the lower alkoxy group has a C14 alkyl radical and may, for example, be methoxy, ethoxy or propoxy; the cycloalkylalkyl group is a C35 cycloalkyl-C,~3 alkyl group, for example, cyclopropylmethyl or cyclobutyl methyl; the straight or branched C17 alkylene radical may, for example, be methylene, ethylene, propylene, methyl-substituted propylene, butylene, dimethyl-substituted butylene or pentylene; the lower alkanoyl may, for example, be formyl, acetyl or propanoyl.
Examples of the 5- or 6-membered heterocyclic ring represented by the formula
are pyrrolidino, piperidino, morpholino, 4-lower alkylpiperazino and 4-arylpiperazino.
The present invention provides, according to one aspect, indoloisoquinolines within the formula (I), which can be used as anti-tumour agents.
Among the compounds of the formula (I), the compounds of the following formula (la) are preferable:
wherein R, and R4 are as defined above, and both
R'2 and R'3 are hydrogen, or either R'2 or R'3 is hydrogen and the other is a group of the formula
(wherein R5 and R6 are as defined above).
Particularly preferred are the compounds of the formula (la) wherein R5 and R6 are, independently of one another, methyl or ethyl, and A is ethylene or propylene.
The present invention provides according to another aspect effective and useful processes for the producing of the compounds of the formula oil).
In a process embodying the present invention, a compound of the formula (I) wherein R2 is other than hydrogen, or a pharmaceutically acceptable acid addition salt thereof, can be prepared by reacting a compound of the formula,
wherein R1, R3 and R4 are as defined above, with a reactive derivative of a compound of the formula, RBOH (veil) wherein R8 is any of the atoms or groups of R2 other than hydrogen, in the presence of a basic condensing agent, or reacting a basic salt of a compound of the formula (V) with a said reactive derivatives; and optionally satisfying the resultant product.
The reactive derivative of the alcohol of the formula (VIII) is preferably a halide, for example, a chloride, bromide or iodide, or a sulfonic ester, for example, an arylsulfonic ester, e.g. a benzenesulfonic ester or p-toluenesulfonic ester or a methanesulfonic ester.
The basic condensing agent may, for example, be any of alkaline metal hydroxides, alkaline metal alkoxides, alkaline metal amides, alkaline metal hydrides, alkyl alkaline metals, and acryl alkaline metals:
Especially suitable basic condensing agents are sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium amide, sodium hydride, butyl lithium and phenyllithium.
The reaction of a process embodying the present invention may be effected at room temperature, but may be accelerated by heating.
The reaction is preferably carried out in an inert solvent. A variety of solvents can be mentioned as suitable solvents, for example, water, alcohols, e.g. methanol, ethanol and butanol, aliphatic and aromatic hydrocarbons, e.g. pentane, hexane, benzene, and toluene, ethers, e.g. ethyl ether, tetrahydrofuran, dioxane, ethylene glycol and dimethyl ether, and aprotic polar solvents for example, dimethylformamide and dimethylsulfoxide.
Alternatively, the reaction may be carried out by subjecting a reaction derivative of an alcohol of the formula (VIII) to a condensation reaction with a basic metal salt of a compound of the formula (V).
A hydroxy indoloisoquinoline of the formula,
wherein R1, R3 and R4 are any of the respective groups given above, or a keto isomer thereof; or a pharmaceutically acceptable acid addition salt of such a compound can be prepared by another process embodying the invention which includes heating an indole-2-isocyanate of the formula,
wherein F1, R3 and R4 are any of the respective groups given above and optionally satisfying the resultant product.
The reaction can be carried out by heating the compound of the formula (VI) at a temperature from 80 to about 2600C.
Alternatively, the reaction can be conducted by heating a compound of the formula (VI) in the presence of a suitable inert organic solvent, preferably at the refluxing temperature thereof.
Inert solvents having a high boiling point can be used to advantage and examples of these are dimethylformamide, ethylene glycol dimethyl ether, quinoline, xylene, anisol, chlorobenzene and nitrobenzene.
An indole-2-isocyanate of the formula (VI) can be obtained by subjecting an indole-2carboxazide of the formula.
wherein R,, R3 and R4 are any of the respective groups given above, to a Curtius rearrangement reaction optionally in the presence of a suitable solvent.
The reaction product of the Curtius rearrangement reaction, a compound of the formula (VI), can be used for the preparation of a compound of the formula (V) without isolation.
Compounds of the formula (la) may be isolated as pharmaceutically acceptable acid addition salts by treatment of the free base with an acid, for example, a mineral acid eg hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, or an organic acid, eg maleic acid, fumaric acid, succinic acid, citric acid, ethanesulfonic acid or ascorbic acid.
Using processes embodying the present invention, the following indoloisoquinolines can, for example, be obtained:
1 0-Chloro-7H-indolo(2,3-c)isoquinolin-5(6H)one
1 0-Nitro-7H-indolo(2,3-c)isoquinolin-5-(6H)one 1 0-Methoxy-7H-indolo(2 ,3-c)isoquinolin- 5(6H)-one 1 -Fluoro-1 0-chloro-7H-indolo(2,3c)isoquinolin-5(6H)-one 7-Methyl-l 0-chloro-7H-indolo(2,3c)isoquinolin-5(6H)-one 7-M ethyl-l 0-nitro-7H-indolo-(2,3c)isoquinolin-5(6H)-one 7-Cyclopropylmethyl-1 0-chloro-7 H-indolo(2,3- c)-isoquinolin-5(6H)-one 7-p-Dimethylaminoethyl-1 0-chloro-7H- indolo(2,3-c)-isoquinolin-5(6H)-one 5-Methoxy-7-methyl-i 0-chloro-7H-indolo- (2,3-c)-isoquinoline 5-Cyclopropylmethyloxy-7-methyl-i O-chloro- 7H-indolo-(2,3-c)isoquinoline 5-AI lyloxy-7-methyl- 1 0-chloro-7 H-indolo(2,3- c)isoquinoline 5-Ethoxymethyloxy-7-methyl-1 0-chloro-7H- indolo(2,3-c)isoquinoline 5-lS-Dimethylaminoethylóxy-7-methyl-10- chloro-7H-indolo(2,3-c)isoquinoline 5-p-Diethylaminoethyloxy-7-methyl-10- chloro-7H-indolo(2,3-c)isoquinoline
5-y-Dimethylaminopropyloxy-7-methyl-1 0chloro-7H-indolo(2,3-c)isoquinoline 5-y-Di methyl aminobutyloxy-7-methyl- O- chloro-7H-indolo(2,3-c)isoquinoline 5-,B-Morpholinoethyloxy-7-methyl-10-chloro- 7H-indolo(2,3-c)isoquinoline 5-p-Hydroxyethyloxy-7-methyl- 10-chloro-7 H- indolo(2,3-c)isoquinoline 5-P-Dimethylam inoethyloxy-7- cyclopropylmethyl- O-chloro-7H-indolo(2,3- c)isoquinoline
Processes embodying the present invention will now be illustrated in more detail with reference to the following Examples.
Example 1
2-lsocyanato-3-(o-fluorophenyl)-5-chloro indole (2.0 g) is heated at 2400--2600C in an oil bath for 20 minutes. After cooling, the resultant solid is washed with ethanol and collected by filtration. Recrystallization from dimethylformamide of the crystals thus obtained gives 0.92 g of 1-fluoro-10-chloro-7H-indolo(2,3- c)isoquinoline-5(6H)-one, melting point > 3000 C.
Example 2
3-Phenyl-5-chloroindole-2-carboxazide (1.32 g) is heated gradually up to 240--2600C and maintained at this temperature for 20 minutes.
After cooling, the resultant solid washed with ethanol and collected by filtration.
Recrystallization from dimethylformamide of the crystals thus obtained gives 0.96 g of 1 0-chloro- 7H-indolo(2,3-c)isoquinolin-5(6H)-one, melting point > 3000 C.
3-Phenyl-5-chloroindole-2-carboxazide is prepared as follows:
3-Phenyl-5-chloroindole-2-carboxylic acid (13.48 g) is added to thionyl chloride (47 g) and the mixture is refluxed for 1 hour. After removal of excess thionyl chloride under reduced pressure, acetone (120 ml) is added to the residue. This is cooled to --1 OC and sodium azide (4.85 g) in water (1 5 ml) is added in one portion with stirring.
The reaction mixture is stirred for a further 40
minutes at 5-i 00C, and 120 ml of water is added. Separation by filtration of the precipitate thus produced gives 16.49 g of 3-phenyl-5chloroindole-2-carboxazide (melting point; 1330C (decomp.)).
Example 3 1 -Methyl-2-isocyanato-3-phenyl-5-nitroindole (3.27 g) is heated at 240-2500C in an oil bath for 3 hours. The resulting crystals are washed with ethanol and collected by filtration to give 3.25 g of 7-methyl-i 0-nitro-7H-indolo(2,3- c)isoquinoline-5(6H)-one, melting point > 3000C.
1 -Methyi-2-isocyanato-3-phenyl-5-nitroindole is prepared as follows:
1 -Methyl-3-phenyl-5-nitroindole-2-carboxaxide (melting point 102-1 060C (decomp.)) (300 mg) is heated at 600C for 8 hours under reduced pressure to give 230 mg of 1-methyl-2- isocyanato-3-phenyl-5-nitroindole, melting point > 2500C.
Example 4 1 -Methyl-2-isocyanato-3-phenyl-5- chloroindole (3.0 g) is heated at 100--1200C in an oil bath for 4 hours. Dimethylformamide (10 ml) is added to the reaction mixture and then refluxed for 30 minutes. After cooling, the precipitate thus produced is separated by filtration and washed with ethanol to give 2.5 g of 7-methyl-1 0-chloro-7H-indolo(2,3-c)isoquinolin5(6H)-one, melting point > 3000C.
1 -Methyl-2-isocya nate-3-phenyl-5chloroindole is prepared as follows: 1 -Methyl-3-phenyl-5-chloroindole-2- carboxazide (meiting point 91-940C (decomp)) is heated at 600C for 10 hours under reduced pressure to give 1 -methyl-2-isocyanato-3-phenyl- 5-chloroindole (melting point 1 500C (decomp)) quantitatively.
Example 5 1 -Methyl-2-isocyanato-3-phenyl-5- chloroindole (3.0 g) in 10 ml of dimethylformamide is heated with stirring at reflux temperature for 1 hour. After cooling, the precipitate thus produced is separated by filtration to give 2.5 g of 7methyl1 O-chloro-7H- indole(2,3-c)isoquinolin-5(6H)-one, melting point > 3000 C.
Example 6 1 -Methyl-3-phenyl-5-chloroindole-2- carboxazide (1.0 g) in 3 ml of dimethylformamide is heated with stirring at reflux temperature for 2 hours. After cooling, the precipitate thus produced is separated by filtration to give 0.76 g of 7 methyl O-chloro-7H-indolo(2,3-c)isoquinolin- 5(6H)-one, melting point > 3000 C.
Example 7
1 -Cyclopropylmethyl-2-isocyanato-3-phehyl5-chloroindole (5.0 g) is heated at 100-i 200C in an oil bath for 4 hours. After cooling, the resulting crystals are washed with ethanol and collected by filtration to give 7 cyclopropylmethyl- 1 0-chloro-7 H-indolo(2,3- c)isoquinolin-5(6H)-one, melting point > 3000 C.
Example 8
To a stirred suspension of 0.089 of 65% sodium hydride (in oil) in 5 ml of dimethylformamide, 0.5 g of 7-methyl-10- chloroindolo(2,3-c)isoquinolin-5(6H)-one is added at room temperature. The reaction mixture is stirred for 30 minutes and 2.5 g of methyl iodide in 30 ml of dimethylformamide is added dropwise thereto at room temperature. After addition, stirring is continued for a. further 16 hours at room temperature and the dimethylformamide is then removed under reduced pressure. The residue is treated with water and extracted with dichloromethane.The organic layer is dried over magnesium sulfate and the solvent is evaporated in vacuo to give 404 mg of 5-methoxy-7-methyl-10-chloro-7H-indolo(2,3- c)isoquinoline, which is recrystallized from ethyl acatate, melting point 1 79-i 80.50C.
Example 9 5-Ethoxy-7-methyl-l 0-chloro-7H-indolo(2,3- c)isoquinoline (melting point 161-1 630C is prepared from 7-methyl-10-chloro-7Hindolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and ethyl bromide by the method described in Example 8.
Example 10 5-Cyclopropylmethyloxy-7-methyl- 1 0-chloro- 7H-indolof2,3-c)isoquinoline (melting point
141-142 C) is prepared from 7-methyl-10- chloro-7H-indolo(2,3-c)isoquinolin-5(6H)one, sodium hydride and cyclopropylmethylbromide by the method described in Example 8.
Example 11 5-lS-Ethoxyethyloxy-7-methyl- O-chloro-7H- indolo(2,3-c)isoquinoline (melting point 93.5- 95.50C) is prepared from 7-methyl-i 0-chloro- 7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium
hydride and ,5-ethoxyethyl bromide by the method described in Example 8.
Example 12 5-Allyloxy-7-methyl- 1 0-chloro-7 H-indolo(2,3- c)isoquinoline (melting point 147-1480C) is prepared from 7-methoxy-i 0-chloro-7H- indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and allyl chloride by the method described in Example 8.
Example 13
5-Vinyloxy-7-methyl- 10-chloro-7H-indolo(2,3- c)isoquinoline (melting point 121-1240C) is prepared from 7-methyl-i 0-chloro-7H- indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and vinyl bromide by the method described in Example 8.
Example 14 5-ssMorpholinoethyloxy-7-methyl- 1 0-chloro- 7H-indolo(2,3-c)isoquinoline (melting point 140-i 42 0C) is prepared from 7-methyl-i 0- chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and ss-morpholinoethyl chloride by the method described in Example 8.
Example 15 5-ss-Dimethyla minoethyloxy-7-methyl- 10
chloro-7H-indolo(2,3-c)isoquinoline (melting point 98--99.5DC) is prepared from 7-methyl-i 0- chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and ,B-dimethylaminoethyl chloride by the method described in Example 8.
Example 16 5-,3-Diethylaminoethyloxy-7-methyl- 10- chloro-7H-indoio(2,3-c)isoquinoline (hydrochloride melting point 236-2370C) is prepared from 7-methyl-i 0-chloro-7H- indolo(2,3-c)isoquinoline-5(6H)one, sodium hydride and p-diethylaminoethyl chloride by the method described in Example 8.
Example 17 5-P-Dimethyiaminoethyloxy-7- cyclopropylmethyl-i 0-chloro-7H-indolo(2,3- c)isoquinoline (meiting point 155-i 570C) is prepared from 7-cyclopropylmethyl-i 0-chloro- 7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and ,B-dimethylaminoethyl chloride by the method described in Example 8.
Claims (11)
1. A compound of the formula
wherein F1 and R4 are each independently of one another, hydrogen, halogen, nitro or lower alkoxy;
R2 and R3 are each independently of one another, hydrogen, lower alkyl lower alkenyl, cycloalkylalkyl or a group of formula
or -A-O-B wherein A is a straight or branched C17 alkylene; F5 and R6 are each, independently of one another, hydrogen or lower alkyl or, together with the adjacent nitrogen atom, form a 5- or 6-membered heterocyclic ring; and B is hydrogen, lower alkyl, lower alkenyl or lower alkanoyl; or when R2 is hydrogen the keto isomer thereof; provided that, when at the same time, each of R, and R4 is hydrogen and R3 is methyl, R2 is other than hydrogen; or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to Claim 1, wherein
R2 and R3 are each hydrogen or either R2 or
R3 is hydrogen and the other group is a group of the formula
wherein A, R5 and Rff are as defined in Claim 1.
3. A compound according to Claim 2, wherein F5 and R6 are each, independently of one another
methyl or ethyl and A is ethylene or propylene.
4. A compound according to Claim 3, wherein
R5 and R6 are each methyl and A is ethylene.
5. A process for preparing a compound of the formula,
wherein R1, R3 and R4 are as defined in Claim 1 and R8 is lower alkyl, lower alkenyl, cycloalkyl or a group of the formula,
or --AA--O-B, wherein A, R5 and B are as defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, which process includes reacting a compound of the formula,
wherein R1, R3 and R4 are as defined in Claim 1 with a reactive derivative of a compound of the formula, R,--OH (veil) wherein R8 is as defined above, and optionally salifying the resultant product.
6. A process for preparing a compound of the formula,
wherein R1 and R4 are each, independently of one another, hydrogen, halogen, nitro or lower alkoxy,
R3 is hydrogen, lower alkyl, lower alkenyl, cycloalkyalkyl or a group of the formula
or --AA--O-B wherein A is a straight or branched C17 alkylene; R5 and R6 are each, independently of one another, hydrogen or lower alkyl or, together with the adjacent nitrogen atom, form a 5- or 6-membered heterocyclic ring; and B is hydrogen, lower alkyl, lower alkenyl or lower alkanoyl or the keto isomer thereof; or an acid addition salt thereof; which process includes heating a compound of the formula,
wherein R1, R3 and R4 are as defined above and optionally salifying the resultant product.
7. A process according to Claim 6 which further includes the preliminary step of preparing a said compound of the formula (V), which step includes subjecting an indole-2-carboxazide of the formula
wherein R1, R3 and R4 are as defined in Claim 6, to a Curtius arrangement reaction optionally in the presence of a solvent.
8. A process according to Claim 7 wherein a compound of the formula (VII) is converted to compound of the formula (V) without isolation of the compound of the formula (VI).
9. The compounds of the formula (I), given and defined in Claim 1, which are specifically disclosed herein.
10. Processes according to any one of Claims 5 to 8 for producing a compound of the formula (I), given and defined in Claim 1, which processes are substantially as herein described and exemplified.
11. Compounds of the formula (I), given and defined in Claim 1, whenever prepared by a process according to any one of Claims 5 to 8 and 10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7826749A GB2025932B (en) | 1978-06-13 | 1978-06-13 | Indoloisoquinolines and processes for producing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7826749A GB2025932B (en) | 1978-06-13 | 1978-06-13 | Indoloisoquinolines and processes for producing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2025932A true GB2025932A (en) | 1980-01-30 |
| GB2025932B GB2025932B (en) | 1982-10-27 |
Family
ID=10497935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7826749A Expired GB2025932B (en) | 1978-06-13 | 1978-06-13 | Indoloisoquinolines and processes for producing them |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2025932B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1603567A2 (en) * | 2003-02-28 | 2005-12-14 | Inotek Pharmaceuticals Corporation | Tetracyclic benzamide derivatives and methods of use thereof |
| US7381722B2 (en) | 2005-02-25 | 2008-06-03 | Inotek Pharmaceuticals Corporation | Tetracyclic amino and carboxamido compounds and methods of use thereof |
| US7652028B2 (en) | 2005-08-24 | 2010-01-26 | Inotek Pharmaceuticals Corporation | Indenoisoquinolinone analogs and methods of use thereof |
| US8119654B2 (en) | 2007-02-28 | 2012-02-21 | Inotek Pharmaceuticals Corporation | Indenoisoquinolinone analogs and methods of use thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6956035B2 (en) | 2001-08-31 | 2005-10-18 | Inotek Pharmaceuticals Corporation | Isoquinoline derivatives and methods of use thereof |
-
1978
- 1978-06-13 GB GB7826749A patent/GB2025932B/en not_active Expired
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1603567A2 (en) * | 2003-02-28 | 2005-12-14 | Inotek Pharmaceuticals Corporation | Tetracyclic benzamide derivatives and methods of use thereof |
| EP1603567A4 (en) * | 2003-02-28 | 2006-10-18 | Inotek Pharmaceuticals Corp | Tetracyclic benzamide derivatives and methods of use thereof |
| JP2007501857A (en) * | 2003-02-28 | 2007-02-01 | イノテック ファーマシューティカルズ コーポレーション | Tetracyclic benzamide derivatives and methods of use thereof |
| US7217709B2 (en) | 2003-02-28 | 2007-05-15 | Inotek Pharmaceuticals Corporation | Tetracyclic benzamide derivatives and methods of use thereof |
| US7381722B2 (en) | 2005-02-25 | 2008-06-03 | Inotek Pharmaceuticals Corporation | Tetracyclic amino and carboxamido compounds and methods of use thereof |
| US7652028B2 (en) | 2005-08-24 | 2010-01-26 | Inotek Pharmaceuticals Corporation | Indenoisoquinolinone analogs and methods of use thereof |
| US8119654B2 (en) | 2007-02-28 | 2012-02-21 | Inotek Pharmaceuticals Corporation | Indenoisoquinolinone analogs and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2025932B (en) | 1982-10-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0179383B1 (en) | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds, a process for their preparation and their use as medicaments | |
| US4695573A (en) | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds | |
| US4263304A (en) | 7 H-indolo[2,3-c]isoquinolines | |
| MXPA03003459A (en) | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof. | |
| GB2025932A (en) | Indoloisoquinolines, and Processes for Producing them | |
| EP0033767A1 (en) | Indolobenzoxazines, processes for preparing and pharmaceutical compositions containing the same | |
| KR100414622B1 (en) | New Tricyclic Derivatives, Their Preparation, Their Use For The Preparation Of Optically Active Or Racemic Colchicine And Thiocolchicine And Analogues Or Derivatives And Intermediates | |
| NO164899B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE IMIDAZOLYLINDOL COMPOUNDS. | |
| US5892047A (en) | Process for the preparation of substituted 4-ethyl-piperidines and an intermediate for the preparation of same | |
| US3839340A (en) | Substituted 1,3,8-triazaspiro{8 4.5{9 decanes | |
| EP0514546B1 (en) | Chromene derivatives, their production and use | |
| EP0233760A1 (en) | Sulfenamide derivatives and their production | |
| US4010280A (en) | Phenoxyalkylamine derivatives and preparation thereof | |
| US3551498A (en) | Dehydrogenation of 10,11-dihydro-5h-dibenzo(a,d)cycloheptene-5-one | |
| EP0300074A1 (en) | Processes and intermediates useful in the preparation of Cis 1,3,4,6,7 llb-Hexa-hydro-7-aryl-2H-pyrazino[2,1-a]isoquinolines | |
| CA1101418A (en) | Indoloisoquinoline derivatives | |
| EP0033214A2 (en) | Process for preparing therapeutically active triazoles | |
| US3113950A (en) | Process for the preparation of cyclohepta [b] pyrrol-8(1h)-one derivatives | |
| EP0002792A1 (en) | 3-Aminopropoxyaryl derivatives, their preparation and pharmaceutical compositions containing them | |
| EP0452094A2 (en) | A method of the preparation of N-hydroxy aspartic acid derivate | |
| US5574160A (en) | Syntheis of benzoquinolinones | |
| US4003930A (en) | 2,3-Trans-5-[3-(amino)-2-hydroxy-propoxy]-1,2,3,4-tetrahydro-3-(or 2)-amino-2-(or 3)-hydroxy-naphthalenes and salts thereof | |
| KR100503845B1 (en) | Process for Converting Nitrogen-Containing Hydroxy Heteroaromatics to Arylamines | |
| US6034241A (en) | Process for converting hydroxy heteroaromatics to arylamines | |
| US3314962A (en) | Ethynylated quinolizinium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |